Bempedoic acid

Usage

Bempedoic acid is prescribed to lower low-density lipoprotein (LDL) cholesterol (“bad” cholesterol) in adults with heterozygous familial hypercholesterolemia (HeFH, a genetic condition causing high cholesterol) or established atherosclerotic cardiovascular disease (ASCVD). It is used in conjunction with lifestyle changes (diet, exercise, weight management) and sometimes with other cholesterol-lowering drugs, particularly when statins are not tolerated or not effective enough. It can also be prescribed to reduce the risk of heart attack and the need for heart-related procedures like bypass surgery or stenting, especially in patients who cannot tolerate statins. It is classified as an adenosine triphosphate-citrate lyase (ACL) inhibitor. Bempedoic acid works by inhibiting ACL, an enzyme crucial for cholesterol synthesis in the liver. By blocking this enzyme, it reduces cholesterol production, consequently lowering LDL-C levels.

Alternate Names

Bempedoic acid is also known as ETC-1002. Brand names include Nexletol (for bempedoic acid alone) and Nexlizet (for bempedoic acid combined with ezetimibe).

How It Works

Pharmacodynamics: Bempedoic acid is a prodrug converted to its active form, ESP-55016, by very-long-chain acyl-CoA synthetase-1 (ACSVL1), an enzyme present predominantly in the liver. ESPE-55016 inhibits ACL, an enzyme upstream of HMG-CoA reductase (the target of statins) in the cholesterol synthesis pathway. This inhibition leads to decreased cholesterol production in the liver, upregulating LDL receptors, and increasing LDL clearance from the bloodstream, hence lowering LDL-C.

Pharmacokinetics:

• Absorption: Bempedoic acid is readily absorbed orally. Food does not significantly affect its absorption.
• Metabolism: Bempedoic acid requires activation by ACSVL1 in the liver. This enzyme is not found in skeletal muscle, hence minimizing the potential for muscle-related side effects associated with statins.
• Elimination: Primarily via hepatic glucuronidation followed by renal and biliary excretion.

Mode of Action: Bempedoic acid’s active form directly inhibits ACL, reducing hepatic cholesterol biosynthesis. This subsequently leads to an increase in LDL receptor expression, which removes LDL-C from circulation.

Receptor Binding/Enzyme Inhibition: The primary mechanism is ACL enzyme inhibition.

Elimination Pathways: Predominantly hepatic metabolism through glucuronidation, followed by renal and biliary excretion.

Dosage

Standard Dosage

Adults: 180 mg orally once daily, with or without food.

Children: The safety and efficacy in children under 18 have not been established.

Special Cases:

• Elderly Patients: No dose adjustment is generally necessary.
• Patients with Renal Impairment: No dose adjustment needed for mild to moderate impairment. Limited data for severe renal impairment (eGFR <30 mL/min/1.73 m²) or end-stage renal disease (ESRD). Close monitoring recommended.
• Patients with Hepatic Dysfunction: No dose adjustment for mild to moderate impairment (Child-Pugh A or B). No data available for severe hepatic impairment (Child-Pugh C). Liver function monitoring recommended.
• Patients with Comorbid Conditions: Caution in patients with a history of gout or hyperuricemia. Bempedoic acid can increase uric acid levels. Close monitoring is essential.

Clinical Use Cases

Bempedoic acid is not indicated for acute clinical situations like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations (e.g., status epilepticus, cardiac arrest). Its role is chronic LDL-C lowering for the prevention of cardiovascular events.

Dosage Adjustments

Dose adjustments may be considered in patients with severe renal impairment or severe hepatic dysfunction, though specific recommendations are limited. Careful monitoring and clinical judgment are advised.

Side Effects

Common Side Effects

• Upper respiratory tract infections
• Back pain
• Muscle spasms or pain
• Abdominal pain or discomfort
• Increased uric acid levels (hyperuricemia) which might lead to gout
• Elevated liver enzymes

Rare but Serious Side Effects

• Tendon rupture or injury (requires immediate discontinuation of the drug)
• Hypersensitivity reactions (rash, itching, hives, swelling, difficulty breathing or swallowing)

Long-Term Effects

Long-term effects are still being studied. Gout can develop with prolonged exposure due to increased uric acid levels.

Adverse Drug Reactions (ADR)

Clinically significant ADRs include tendon rupture, hypersensitivity reactions, and severe hyperuricemia leading to gout. These require immediate medical intervention.

Contraindications

• Hypersensitivity to bempedoic acid or any of its components.
• Pregnancy.
• Breastfeeding.
• Concomitant use with high-dose simvastatin (>40 mg/day; reduce to 20 mg/day if co-administration is necessary) or high-dose pravastatin (>40 mg/day if co-administration is necessary).

Drug Interactions

• Statins: Increased risk of myopathy with simvastatin >20 mg/day or pravastatin >40 mg/day.
• Other Cholesterol-Lowering Drugs: Can be safely combined with ezetimibe, which has a synergistic LDL-lowering effect. Minor interactions with atorvastatin and rosuvastatin have been observed, but dose adjustments are typically not required.
• Other Drugs: Consult a drug interaction database for a full list as numerous potential interactions exist, including with some antibiotics, antivirals, antifungals, and immunomodulators.
• Food and Lifestyle Factors: No significant interactions known. However, some interacting medications may have interactions with food, particularly grapefruit juice.

Pregnancy and Breastfeeding

• Pregnancy: Contraindicated. Bempedoic acid can lower cholesterol levels necessary for fetal development and may cause fetal harm.
• Breastfeeding: Contraindicated. It is unknown if bempedoic acid passes into breast milk, but due to potential risk to the infant, it’s best avoided.

Drug Profile Summary

• Mechanism of Action: ACL inhibitor, reducing hepatic cholesterol synthesis and increasing LDL receptor expression.
• Side Effects: Common: upper respiratory infections, back pain, muscle spasms, abdominal pain, hyperuricemia, elevated liver enzymes. Serious: tendon rupture, hypersensitivity.
• Contraindications: Hypersensitivity, pregnancy, breastfeeding, concomitant use with high-dose simvastatin or pravastatin.
• Drug Interactions: Statins (especially simvastatin and pravastatin), other drugs metabolized by the liver (consult drug interaction database).
• Pregnancy & Breastfeeding: Contraindicated.
• Dosage: Adults: 180 mg orally once daily.
• Monitoring Parameters: LDL-C, uric acid, liver function tests.

Popular Combinations

Bempedoic acid is often combined with ezetimibe (Nexlizet). This combination provides synergistic LDL-C lowering.

Precautions

• General Precautions: Monitor for signs of gout, tendon rupture, and liver dysfunction.
• Specific Populations: Avoid in pregnancy and breastfeeding. Caution in patients with renal or hepatic impairment. Children: safety and efficacy not established.
• Lifestyle Considerations: Maintain a healthy diet and exercise program.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Bempedoic acid?

A: The standard adult dosage is 180 mg orally once daily. No dose adjustment is usually needed for elderly patients or those with mild to moderate renal or hepatic impairment. However, close monitoring is recommended in these populations. No data available for severe hepatic impairment and limited data for severe renal impairment or ESRD.

Q2: How does Bempedoic acid differ from statins?

A: While both lower LDL-C, they target different enzymes in the cholesterol synthesis pathway. Bempedoic acid inhibits ACL, while statins inhibit HMG-CoA reductase. Bempedoic acid is a prodrug activated only in the liver, potentially reducing the risk of muscle-related side effects seen with statins.

Q3: Can Bempedoic acid be used with statins?

A: Yes, but caution is necessary with simvastatin and pravastatin. Limit simvastatin to 20 mg/day (or 40 mg/day with close monitoring if benefits outweigh the risks), and use pravastatin cautiously. Minor interactions are possible with other statins but dose adjustments are usually unnecessary.

Q4: What are the most common side effects?

A: Upper respiratory tract infections, back pain, muscle spasms, increased uric acid, elevated liver enzymes, and abdominal pain.

Q5: What are the serious side effects to watch out for?

A: Tendon rupture (discontinue immediately) and hypersensitivity reactions.

Q6: Can pregnant or breastfeeding women take Bempedoic acid?

A: No, it is contraindicated in both pregnancy and breastfeeding due to potential fetal harm and unknown effects on infants.

Q7: What if a patient has a history of gout?

A: Bempedoic acid can raise uric acid levels and may trigger gout attacks. Monitor uric acid levels and consider prophylactic measures for gout if necessary.

Q8: How long does it take for Bempedoic acid to work?

A: Significant LDL-C reductions are usually seen within 2-4 weeks of starting therapy.

Q9: Is there a generic version available?

A: As of today, February 16, 2025, there is no generic version of Bempedoic acid available.

Q10: Does Bempedoic acid interact with other medications?

A: Yes, it can interact with various medications, including some statins, other lipid-lowering therapies, and certain other drugs metabolized in the liver. Always consult a drug interaction database or pharmacist for a full assessment and to ensure patient safety.